Much of the recent work in the neurobiology of emotion has divided emotion into two categories of positive and negative emotion. Positive emotions involving high levels of arousal often occur in the context of the anticipation of reward, while negative emotions, which also involve high levels of arousal often occur in the context of the anticipation of punishment. In addition, comparative studies have implicated a ventral forebrain dopaminergic pathway in the anticipation of reward, and most of the animal models of substance abuse focus heavily on the importance of mesolimbic dopamine projections in the neural circuitry underlying drug craving. Thus, we have sought to characterize neural activity associated with the anticipation of rewards and punishments, particularly in brain dopamine system. In order to investigate the neural basis of reward and punishment we have used functional magnetic resonance imaging (fMRI) to measure brain activation during monetarily rewarded approach and avoidance behavior in humans. Specifically, we examined whether ventral forebrain dopamine projection areas were activated prior to motor behavior, during anticipation of reward and punishment, as opposed to during responses following reward and punishment. During the approach interval, subjects saw a cue indicating that they could either win money or not, waited a variable delay, and then pressed a button in response presentation of a target. If subjects responded before the target following the reward cue disappeared, they won $5.00, $1.00, or $.20 whereas their response to the neutral target did not affect their total. During the active avoidance task, subjects were given $20.00 and responded to targets that followed either a punishment cue or a neutral cue. If they failed to respond before the disappearance of the target following the punishment cue, they lost $5.00, $1.00, or $.20 whereas their response to the neutral target again did not affect their total. T2*-weighted gradient echoplanar MR volumes depicting blood oxygenation level dependent (BOLD)-contrast were acquired using a 1.5 or 3.0 Tesla GE System. After correcting for in-plane motion, individual voxel activations were correlated with an ideal waveform corresponding to the expected activation time course using the AFNI software package. The ideal waveform consisted of the task On-Off waveform convoluted with the hemodynamic response function. Anticipation of reward activated striatal areas (caudate, putamen) and mesial forebrain areas (anterior cingulate, mesial prefrontal cortex, and thalamic regions). Anticipation of punishment also activated these regions relative to anticipation of no monetary outcome. However, anticipation of reward but not punishment produced activation in the nucleus accumbens. Magnitude of nucleus accumbens activation predicted the amount of positive emotion subjects reported feeling when the cues signaling monetary reward. We also separately examined reward anticipation and outcomes with event-related fMRI. This study confirmed that the nucleus accumbens was primarily recruited by anticipation of monetary reward. This activation subsided during delivery of rewarding outcomes, and moreover, nucleus accumbens activity was suppressed when anticipated rewards were not obtained. Reward anticipation did not activate the ventro-medial prefrontal cortex (VMFC), but nonoccurrence of anticipated rewards did suppress VMFC activity. Deactivation of these regions during reward nondelivery is consistent with primate electrophysiological recordings showing decreased midbrain dopamine neural firing during reward omission. Studies are currently ongoing to compare the brain response to anticipation of working to gain reward or to avoid punishment in adolescents with and without a family history of alcoholism or substance abuse. These studies have shown that adolescents activate the same brain circuit during anticipation of woorking for reward as adults do, but that the magnitude of the activation is less than the magnitude seen in adults. In addition, we have also begun comparing brain motivation circuits in alcoholics and controls. Initial results from this work suggest that alcoholics studied three weeks from their last drink also shown a blunted response in the nucleus accumbens during the anticipation of working for reward as well as during the notification of successful outcome. This blunting is greatest in alcoholics who do not relaspe in the six months following the scan. We have also developed a series of fMRI tasks which allow us to examine brain BOLD response during a risk taking task in which financial reward is determined by how much risk aindividual is willing to endure. This task shows robust BOLD activation in the cingulate cortex. Studies are also underway to examine the relationship between the magnitude of effort required to complete a task, uncertainity of reward and the magnitude of BOLD activation in the ventral stiatum. The effect of pharmacological probes such as amphetamine, dopamine depletion and intravenously administered ethanol are also being investigated. Prliminary evidence suggests that intravenously administered ethanol is associated with an increase in BOLD signal in the ventral forebrain, including extended amygdala and ventral striatum.